Enhancement Of Slow-wave Sleep Research Articles

Propofol enhancement of slow wave sleep to target the nexus of geriatric depression and cognitive dysfunction: protocol for a phase I open label trial

IntroductionLate-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow...

A wearable EEG system for closed-loop neuromodulation of sleep-related oscillations

Objective. Healthy sleep plays a critical role in general well-being. Enhancement of slow-wave sleep by targeting acoustic stimuli to particular phases of delta (0.5–2 Hz) waves has shown promise as a non-invasive approach to improve sleep quality. Closed-loop stimulation during other sleep phases targeting oscillations at higher frequencies such as theta (4–7 Hz) or alpha (8–12 Hz) could be another approach to realize additional health benefits. However, systems to track and deliver stimulation relative to the instantaneous phase of electroencephalogram (EEG) signals at these higher frequencies have yet to be demonstrated outside of controlled laboratory settings. Approach. Here we examine the feasibility of using an endpoint-corrected version of the Hilbert transform (ecHT) algorithm implemented on a headband wearable device to measure alpha phase and deliver phase-locked auditory stimulation during the transition from wakefulness to sleep, during which alpha power is greatest. First, the ecHT algorithm is implemented in silico to evaluate the performance characteristics of this algorithm across a range of sleep-related oscillatory frequencies. Secondly, a pilot sleep study tests feasibility to use the wearable device by users in the home setting for measurement of EEG activity during sleep and delivery of real-time phase-locked stimulation. Main results. The ecHT is capable of computing the instantaneous phase of oscillating signals with high precision, allowing auditory stimulation to be delivered at the intended phases of neural oscillations with low phase error. The wearable system was capable of measuring sleep-related neural activity with sufficient fidelity for sleep stage scoring during the at-home study, and phase-tracking performance matched simulated results. Users were able to successfully operate the system independently using the companion smartphone app to collect data and administer stimulation, and presentation of auditory stimuli during sleep initiation did not negatively impact sleep onset. Significance. This study demonstrates the feasibility of closed-loop real-time tracking and neuromodulation of a range of sleep-related oscillations using a wearable EEG device. Preliminary results suggest that this approach could be used to deliver non-invasive neuromodulation across all phases of sleep.

0074 Investigating the Impacts of Pharmacological Slow-Wave Sleep Enhancement on Cognition in an Alzheimer's Disease Model

Abstract Introduction Alzheimer’s disease (AD) is a debilitating and irreversible neurodegenerative disease associated with major disruptions to sleep. Recent works point to a strong bidirectional relationship between loss of slow-wave sleep (SWS), the deepest sleep stage, and the pathological and cognitive features of AD. Here, we investigate the impacts of chronic pharmacological SWS enhancement with gaboxadol, a delta GABAA receptor agonist, on cognitive performance the APP/PS1 mouse model of AD. Currently, we are assessing the impacts of this intervention on Abeta plaque burden. Methods Using electroencephalography (EEG), we first assessed if gaboxadol is capable of stimulating SWS sleep in 6-month-old AD mice. Next, 6-month-old control (CTRL) or AD mice received gaboxadol 5x/week for 4 weeks at the start of the light cycle. Groups underwent subsequent testing in the open field (OF), Y-maze, and contextual fear conditioning (CFC) assays (n = 8-9 mice per group). Data were analyzed using two- or three-way ANOVAs, with repeated measures when appropriate. Results Our EEG studies demonstrate that gaboxadol (6 mg/kg) significantly enhances SWS/NREM from baseline (p < 0.0308). Gaboxadol did not impact gross locomotor behavior assessed by distance travelled in the in the OF. However, rearing was decreased in AD mice compared to CTRL mice (p < 0.0128). In the Y-maze, gaboxadol significantly increased time spent in the novel arm in CTRL (p < 0.0386) but not AD mice. We did not find significant effects of gaboxadol on memory recall in the CFC assay. Conclusion Chronic pharmacological stimulation of SWS using gaboxadol does not show robust cognition-enhancing effects in APP/PS1 mice, but may be cognitively enhancing in CTRL mice. It is possible that longer treatment duration is necessary to rescue cognitive deficits in AD mice. Support (if any) NIA: 5R21AG064774-02 T32 GM7367-46

Targeting Slow Wave Sleep Deficiency in Late-Life Depression: A Case Series With Propofol

Slow wave sleep (SWS), characterized by large electroencephalographic oscillations, facilitates crucial physiologic processes that maintain synaptic plasticity and overall brain health. Deficiency in older adults is associated with depression and cognitive dysfunction, such that enhancing sleep slow waves has emerged as a promising target for novel therapies. Enhancement of SWS has been noted after infusions of propofol, a commonly used anesthetic that induces electroencephalographic patterns resembling non-rapid eye movement sleep. This paper 1) reviews the scientific premise underlying the hypothesis that sleep slow waves are a novel therapeutic target for improving cognitive and psychiatric outcomes in older adults, and 2) presents a case series of two patients with late-life depression who each received two propofol infusions. One participant, a 71-year-old woman, had a mean of 2.8 minutes of evening SWS prior to infusions (0.7% of total sleep time). SWS increased on the night after each infusion, to 12.5 minutes (5.3% of total sleep time) and 24 minutes (10.6% of total sleep time), respectively. Her depression symptoms improved, reflected by a reduction in her Montgomery-Asberg Depression Rating Scale (MADRS) score from 26 to 7. In contrast, the other participant, a 77-year-old man, exhibited no SWS at baseline and only modest enhancement after the second infusion (3 minutes, 1.3% of total sleep time). His MADRS score increased from 13 to 19, indicating a lack of improvement in his depression. These cases provide proof-of-concept that propofol can enhance SWS and improve depression for some individuals, motivating an ongoing clinical trial (ClinicalTrials.gov NCT04680910).

Enhancement of slow wave sleep and declarative memory consolidation with pink noise acoustic stimulation during sleep

Enhancement of slow wave sleep and declarative memory consolidation with pink noise acoustic stimulation during sleep

Hypnotic enhancement of slow-wave sleep increases sleep-associated hormone secretion and reduces sympathetic predominance in healthy humans

Sleep is important for normal brain and body functioning, and for this, slow-wave sleep (SWS), the deepest stage of sleep, is assumed to be especially relevant. Previous studies employing methods to enhance SWS have focused on central nervous components of this sleep stage. However, SWS is also characterized by specific changes in the body periphery, which are essential mediators of the health-benefitting effects of sleep. Here we show that enhancing SWS in healthy humans using hypnotic suggestions profoundly affects the two major systems linking the brain with peripheral body functions, i.e., the endocrine and the autonomic nervous systems (ANS). Specifically, hypnotic suggestions presented at the beginning of a 90-min afternoon nap to promote subsequent SWS strongly increased the release of growth hormone (GH) and, to a lesser extent, of prolactin and aldosterone, and shifted the sympathovagal balance towards reduced sympathetic predominance. Thus, the hypnotic suggestions induced a whole-body pattern characteristic of natural SWS. Given that the affected parameters regulate fundamental physiological functions like metabolism, cardiovascular activity, and immunity, our findings open up a wide range of potential applications of hypnotic SWS enhancement, in addition to advancing our knowledge on the physiology of human SWS.

0279 Thermoneutral temperature exposure increases slow-wave sleep in the 3xTg-AD mouse model of Alzheimer’s Disease

Abstract Introduction There is growing evidence that disordered sleep, which is known to be associated with Alzheimer’s disease (AD), may accelerate neuropathology, thus promoting a vicious cycle. Strategies for improving sleep quality may slow disease progression. Here we investigate the feasibility of sleep enhancement through ambient temperature regulation and examine the effect on amyloid pathology. Methods Female 3xTg-AD mice (~12 m.o.) were instrumented for EEG/EMG monitoring. After a week-long baseline, one half of the mice (n=8, EXPT) were exposed to stepwise diurnal increases in ambient temperature (Ta) to reach 30oC (thermoneutral for mice) during the light phase while the rest (n=8, CTRL) remained at room temperature (22oC). Vigilance state – i.e., Wake, REM, NREM, and slow wave sleep (SWS) within NREM – was scored in 4-second epochs and sleep metrics were computed. Results SWS percentage became significantly greater (p<0.05) in the light phase for EXPT mice over the course of treatment. These effects suggest better sleep consolidation and greater sleep depth with thermoneutral warming. After four weeks of treatment, the animals were euthanized, and the brains removed to assay amyloid pathology by ELISA. We found that thermoneutral warming caused a significant reduction in both Aβ40 and Aβ42 in the hippocampus, but not in the cortex. Conclusion These data imply that thermoneutral warming might have some regional specificity in its effects. The effects appear to be specific to some brain areas more than others, with implications for the cognitive and neuropathologic changes found in AD. Furthermore, since SWS and REM support memory, future studies should investigate the effects of thermoneutral enhancement of SWS and REM on cognition. Support (If Any) R01AG068215; seed funds UKY Department of Neuroscience

0104 Acoustic enhancement of slow-wave sleep in healthy adolescents

Abstract Introduction Adolescents have a stable sleep-need of between 9-10 hours a night, yet a pattern of markedly restricted sleep duration, particularly on school nights, has given rise to an epidemic of sleep deprivation in this population. As demonstrated by large numbers of studies, insufficient, irregular, and/or poor-quality sleep is a risk factor for both mental health problems and learning difficulties. Enhancing slow-wave sleep through non-pharmacological means may be a mechanism for alleviating daytime functional deficits in youth. In this study, we tested the feasibility of enhancing slow-wave sleep in healthy adolescents using a closed-loop, sleep-wearable device (SmartSleep, Phillips-Respironics) which monitors the EEG signal to automatically detect sleep stages, slow-waves, and micro-arousals to deliver acoustic stimulation to enhance SWA. Methods Seventeen healthy adolescents (15.5±1.8 years; 11 female) who endorsed sleep restriction and symptoms of daytime sleepiness participated in a randomized, cross-over study. Participation included wearing SmartSleep for two consecutive 4-night periods at home—one period with acoustic stimulation (STIM) and one without (SHAM). During STIM, SmartSleep monitors the EEG in real-time and delivers acoustic tones (50 ms, 1 second interval between) through embedded headphones at an intensity dynamically modulated by sleep depth. Stimulation is stopped when an arousal or sleep stage-shift is detected. During SHAM recording, the same stimulation protocol is applied with tones played at zero volume. Results No differences were observed in any measure of sleep architecture. A mixed effects linear regression model was used to analyze the impact of condition (STIM vs SHAM) on both cumulative and average SWA during N2N3 and N3 sleep. At the group level, cumulative SWA during N2N3 and average SWA during N3 were significantly increased in STIM relative to SHAM (p=0.01; p=0.02, respectively), while age (p=0.67) and sex (p=0.71) had no effect. Despite the significant group effects, not all youth were responders; an average increase in cumulative SWA (11.5 ± 7.1%) in the STIM condition was observed in 12/17 participants. Conclusion Consecutive nights of acoustic stimulation enhanced SWA in otherwise healthy, sleep-restricted adolescents. These data suggest that acoustic stimulation during sleep may be a viable method for optimizing slow-wave activity and minimizing the emotional and cognitive consequences of sleep restriction during this sensitive developmental period. Support (If Any)

Two novel mouse models of slow-wave-sleep enhancement in aging and Alzheimer's disease.

Aging and Alzheimer's disease (AD) are both associated with reduced quantity and quality of the deepest stage of sleep, called slow-wave-sleep (SWS). Slow-wave-sleep deficits have been shown to worsen AD symptoms and prevent healthy aging. However, the mechanism remains poorly understood due to the lack of animal models in which SWS can be specifically manipulated. Notably, a mouse model of SWS enhancement has been recently developed in adult mice. As a prelude to studies assessing the impact of SWS enhancement on aging and neurodegeneration, we first asked whether SWS can be enhanced in animal models of aging and AD. The chemogenetic receptor hM3Dq was conditionally expressed in GABAergic neurons of the parafacial zone of aged mice and AD (APP/PS1) mouse model. Sleep-wake phenotypes were analyzed in baseline condition and following clozapine-N-oxide (CNO) and vehicle injections. Both aged and AD mice display deficits in sleep quality, characterized by decreased slow wave activity. Both aged and AD mice show SWS enhancement following CNO injection, characterized by a shorter SWS latency, increased SWS amount and consolidation, and enhanced slow wave activity, compared with vehicle injection. Importantly, the SWS enhancement phenotypes in aged and APP/PS1 model mice are comparable to those seen in adult and littermate wild-type mice, respectively. These mouse models will allow investigation of the role of SWS in aging and AD, using, for the first time, gain-of SWS experiments.

The therapeutic properties of ketogenic diets, slow-wave sleep, and circadian synchrony.

To summarize emerging connections between sleep, ketogenic diets, and health. Mechanisms involved in the therapeutic benefits of ketogenic diets continue to be elucidated. Concurrently, the importance of sleep quality and circadian rhythms in their effects on metabolic and cognitive health is increasingly appreciated. Advances in the understanding of the actions of adenosine, nicotinamide adenine dinucleotide, and slow-wave sleep underscore connections between these areas of research. Many molecular pathways activated during ketogenic diets are known to modulate sleep-wake cycles, circadian rhythms, and sleep stages. Ketogenic diets often have beneficial effects on sleep at the same time as having beneficial effects on particular medical conditions. Enhancement of slow-wave sleep and rejuvenation of circadian programming may be synergistic with or causally involved in the benefits of ketogenic diets.

Acoustic enhancement of slow wave sleep on consecutive nights improves alertness and attention in chronically short sleepers

IntroductionChronic sleep restriction has been linked to occupational errors and motor vehicle crashes. Enhancing slow wave sleep may alleviate some of the cognitive deficits associated with chronic sleep restriction. However, the extent to which acoustic stimulation of slow wave activity (SWA) may improve alertness and attention is not well established, particularly with respect to consecutive nights of exposure. MethodsTwenty-five healthy adults (32.9 ± 8.2 years; 16 female) who self-restricted their sleep during workdays participated in a randomized, double-blind, cross-over study. Participants wore an automated acoustic stimulation device for two consecutive nights. Acoustic tones (50 ms long) were delivered on the up-phase of the slow wave first and then at constant 1-s inter-tone-intervals once N3 was identified (STIM), until an arousal or shift to another sleep stage occurred, or at inaudible decibels during equivalent stimulation periods (SHAM). Subjective alertness/fatigue (KSS, Samn-Perelli) was assessed across both days, and objective measures of alertness (MSLT) and attention (PVT) were assessed after two nights of stimulation. ResultsAfter one night of acoustic stimulation, increased slow wave energy was observed in 68% of participants, with an average significant increase of 17.7% (p = 0.01), while Night 2 was associated with a 22.2% increase in SWA (p = 0.08). SWE was highly stable across the two nights of STIM (ICC 0.93, p < 0.001), and around half (56%) of participants were consistently classified as responders (11/25) or non-responders (3/25). Daytime testing showed that participants felt more alert and awake following each night of acoustic stimulation (p < 0.05), with improved objective attention across the day following two nights of acoustic stimulation. DiscussionConsecutive nights of acoustic stimulation enhanced SWA on both nights, and improved next day alertness and attention. Given large individual differences, we highlight the need to examine both the long-term effects of stimulation, and to identify inter-individual differences in acoustic stimulation response. Our findings suggest that the use of an acoustic device to enhance slow wave sleep may alleviate some of the deficits in alertness and attention typically associated with sleep restriction.

Modulating overnight memory consolidation by acoustic stimulation during slow-wave sleep: a systematic review and meta-analysis.

The low-frequency high-amplitude oscillations of slow-wave sleep (SWS) are considered to promote the consolidation of episodic memory. Previous research suggests that sleep slow waves can be entrained and enhanced by presenting short acoustic stimuli to the up-states of endogenous waves. Several studies have investigated the effects of these increases in slow-wave activity on overnight memory consolidation, with inconsistent results. The aim of this meta-analysis was to evaluate the accumulated evidence connecting acoustic stimulation during sleep to episodic memory consolidation. A systematic literature search was conducted in October 2020 using PubMed, Web of Science, and PsycInfo. The main study inclusion criteria were the application of acoustic slow wave enhancement in healthy participants and an assessment of pre- and post-sleep episodic memory performance. Effect sizes were pooled using a random-effects model. A total of 10 primary studies with 11 experiments and 177 participants were included. Results showed a combined effect size (Hedges' g) of 0.25 (p = 0.07). Subgroup models based on young adults (n = 8), phase-locked stimulation approaches (n = 8), and their combination (n = 6) showed combined effect sizes of 0.31 (p = 0.051), 0.36 (p = 0.047), and 0.44 (p = 0.01), respectively. There was no indication of publication bias or bias in individual studies. Acoustic enhancement of SWS tends to increase the overnight consolidation of episodic memory but effects remain small and-with the exception of subgroup models-at trend levels. Currently, the evidence is not sufficient to recommend the use of commercially available devices.

Acoustic slow wave sleep enhancement via a novel, automated device improves executive function in middle-aged men.

As slow-wave activity (SWA) is critical for cognition, SWA-enhancing technologies provide an exciting opportunity to improve cognitive function. We focus on improving cognitive function beyond sleep-dependent memory consolidation, using an automated device, and in middle-aged adults, who have depleted SWA yet a critical need for maximal cognitive capacity in work environments. Twenty-four healthy adult males aged 35-48 years participated in a randomized, double-blind, cross-over study. Participants wore an automated acoustic stimulation device that monitored real-time sleep EEG. Following an adaptation night, participants were exposed to either acoustic tones delivered on the up phase of the slow-wave (STIM) or inaudible "tones" during equivalent periods of stimulation (SHAM). An executive function test battery was administered after the experimental night. STIM resulted in an increase in delta (0.5-4 Hz) activity across the full-night spectra, with enhancement being maximal at 1 Hz. SWA was higher for STIM relative to SHAM. Although no group differences were observed in any cognitive outcomes, due to large individual differences in SWA enhancement, higher SWA responders showed significantly improved verbal fluency and working memory compared with nonresponders. Significant positive associations were found between SWA enhancement and improvement in these executive function outcomes. Our study suggests that (1) an automated acoustic device enhances SWA; (2) SWA enhancement improves executive function; (3) SWA enhancement in middle-aged men may be an important therapeutic target for enhancing cognitive function; and (4) there is a need to examine interindividual responses to acoustic stimulation and its effect on subsequent cognitive function. This study has been registered with the Australian New Zealand Clinical Trials Registry. "The efficacy of acoustic tones in slow-wave sleep enhancement and cognitive function in healthy adult males". https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371548&isReview=true. ACTRN12617000399392.

Long-Term Trazodone Use and Cognition: A Potential Therapeutic Role for Slow-Wave Sleep Enhancers.

Background: Recent studies reveal an association between slow-wave sleep (SWS), amyloid-β aggregation, and cognition.Objective: This retrospective study examines whether long-term use of trazodone, an SWS enhancer, is associated with delayed cognitive decline.Methods: We identified 25 regular trazodone users (mean age 75.4±7.5; 9 women, 16 men) who carried a diagnosis of Alzheimer’s dementia, mild cognitive impairment, or normal cognition, and 25 propensity-matched trazodone non-users (mean age 74.5±8.0; 13 women, 12 men), accounting for age, sex, education, type of sleep deficit (hypersomnia, insomnia, parasomnia), diagnosis, and baseline Mini-Mental State Examination (MMSE). Longitudinal group differences in cognitive testing were evaluated through repeated measures tests over an average inter-evaluation interval of four years.Results: Trazodone non-users had 2.6-fold faster decline MMSE (primary outcome) compared to trazodone users, 0.27 (95% confidence interval [CI]: 0.07–0.48) versus 0.70 (95% CI: 0.50–0.90) points per year (p = 0.023). The observed effects were especially associated with subjective improvement of sleep complaints in post-hoc analyses (p = 0.0006). Secondary outcomes of other cognitive and functional scores had variable worsening in non-users and varied in significance when accounting for co-administered medications and multiple comparisons. Trazodone effects on MMSE remained significant within participants with AD-predicted pathology, with 2.4-fold faster decline in non-users (p = 0.038).Conclusions: These results suggest an association between trazodone use and delayed cognitive decline, adding support for a potentially attractive and cost-effective intervention in dementia. Whether the observed relationship of trazodone to cognitive function is causal or an indirect marker of other effects, such as treated sleep disruption, and if such effects are mediated through SWS enhancement requires confirmation through prospective studies.

Executive function improves following acoustic slow wave sleep enhancement with a novel, automated device

Executive function improves following acoustic slow wave sleep enhancement with a novel, automated device

0336 Optimal Phase of Slow Wave Auditory Stimulation

Auditory closed loop stimulation as a non-pharmacological method for enhancement of slow wave sleep (SWS) has been proven effective. This work focuses on a key parameter of this methodology: the precise phase of delivery of the auditory pulse. Data from a set of 10 subjects were obtained overnight using a single electrode (frontal region) EEG device (Deepwave Cogniband). A Phase Locked Loop (PLL) algorithm tracked the slow waves (SW) identifying specific auditory stimulation target phases. The phase periodically changed (every 30 seconds) over a set of 6 preselected target phases during a single night of sleep. Data was filtered in the delta band range (0.5–4 Hz). Percent difference of the root mean square of the EEG amplitude between consecutive stimulation segments (lasting 5 PLL oscillations) and segments of sham data was calculated offline. We produced a circular diagram with each single block-pair (on and off) for each subject and the entire subject group as a function of EEG slow wave phase to study the function of phase in the stimulation procedure. We found an optimal range of phases around the angle 340 (+- 20 degrees) in the close-loop auditory stimulations of SW. Angles at 90 degree from this phase produce a slight decrease in SW amplitude. Interestingly, the order in which the phase changes were presented (clockwise vs anti-clockwise) seems to produce different amplitude effects (larger in anti-clockwise order by a factor of 2 for similar phase range). Slow wave enhancement via auditory stimulation is very sensitive to the phase of the SW oscillation. The order of presentation of the pulses is different in the (clock-wise vs anti-clockwise direction) seems to affect the amplitude. This phenomenon needs to be explored further as it could elucidate important aspects of SW physiology. The study was conducted with private fundings from Deep Knowledge Ventures.

Association between Long-Term Slow-Wave Sleep Enhancement and Cognitive Performance (P6.073)

Association between Long-Term Slow-Wave Sleep Enhancement and Cognitive Performance (P6.073)

Sleep architecture and memory consolidation in children with focal epilepsy

BackgroundCognitive impairment is a major comorbidity in children with epilepsy. During the past decade, evidence has emerged that the consolidation of declarative memory (memory for facts and events) is promoted by slow-wave sleep. The aim of this study was to investigate whether sleep architecture is disrupted in children with epilepsy, and whether this disruption impacts on memory consolidation in these children compared with healthy children. MethodsA within-subject comparison of memory retention across similar length intervals overnight (sleep condition) or daytime (wake condition) was performed in 20 children with focal epilepsy (aged 6–16 years) and 19 healthy, age-matched children (controls). For each condition, participants learned a list of semantically related word pairs for cued recall after the interval. Patients participated during admission for video electroencephalogram (EEG) telemetry, whereas controls underwent ambulatory EEG polysomnography across the sleep condition. FindingsChildren with epilepsy had less rapid eye movement sleep (ANCOVA with age as covariate F=8·2, p=0·007) and more stage 2 sleep (F=5·335, p=0·027) than did controls, but a similar amount of slow-wave sleep and stage 1 sleep. Memory retention was greater in the sleep than the wake condition (repeated measures ANOVA F=7·876, p=0·008) and there was no significant interaction effect with group (patients vs controls) or order of conditions. The difference in memory retention scores between the sleep and wake conditions correlated with the proportion of time that the child spent in slow-wave sleep across the total sample (Pearson r=0·461, p=0·003). This association was significant in controls (r=0·546, p=0·051), but did not reach significance in children with epilepsy, and was not altered after controlling for age. InterpretationPatients with focal epilepsy show benefit to memory consolidation with sleep similar to that seen in healthy individuals, despite the underlying disease and effects of treatment. The association with slow-wave sleep, which is preserved at the expense of rapid eye movement sleep, also seems robust. Our findings suggest that the enhancement of slow-wave sleep—by behavioural, pharmacological, or physical means—has the potential to improve cognitive outcome in this patient group. FundingAction Medical Research, Reta Lila Howard Foundation.

Effects of slow-wave sleep enhancement by the difference between the hypnotics on glucose tolerance and the cognitive function next morning in healthy young males

Effects of slow-wave sleep enhancement by the difference between the hypnotics on glucose tolerance and the cognitive function next morning in healthy young males

Kappa-opioid receptors in the caudal nucleus tractus solitarius mediate 100 hz electroacupuncture-induced sleep activities in rats.

Previous results demonstrated that 10 Hz electroacupuncture (EA) of Anmian acupoints in rats during the dark period enhances slow wave sleep (SWS), which involves the induction of cholinergic activity in the caudal nucleus tractus solitarius (NTS) and subsequent activation of opioidergic neurons and μ-receptors. Studies have shown that different kinds of endogenous opiate peptides and receptors may mediate the consequences of EA with different frequencies. Herein, we further elucidated that high-frequency (100 Hz)-EA of Anmian enhanced SWS during the dark period but exhibited no direct effect on rapid eye movement (REM) sleep. High-frequency EA-induced SWS enhancement was dose-dependently blocked by microinjection of naloxone or κ-receptor antagonist (nor-binaltorphimine) into the caudal NTS, but was affected neither by μ- (naloxonazine) nor δ-receptor antagonists (natatrindole), suggesting the role of NTS κ-receptors in the high-frequency EA-induced SWS enhancement. Current and previous results depict the opioid mechanisms of EA-induced sleep.